Nomenclature: mGlu8 receptor

Family: Metabotropic glutamate receptors

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing. 

Contents

Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 908 7q31.3-q32 GRM8 glutamate receptor, metabotropic 8 29,38
Mouse 7 908 6 A3 Grm8 glutamate receptor, metabotropic 8 9
Rat 7 908 4q22 Grm8 glutamate receptor, metabotropic 8 28
Previous and Unofficial Names
GRM8
Gprc1h
mGluR8
GLUR8
mGlu8
mGluR8b
mGlur
G protein-coupled receptor family C group 1 member H
G protein-coupled receptor, family C, group 1, member H
glutamate receptor, metabotropic 8
metabotropic glutamate receptor 8
metabotropic glutamate receptor subtype 8b
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
L-glutamic acid
Comments: Other endogenous ligands include L-aspartic acid, L-SOP, NAAG and L-cysteine sulphinic acid
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]AP4 Hs Full agonist 6.6 – 6.7 pKd 21
pKd 6.6 – 6.7 [21]
(S)-3,4-DCPG Hs Full agonist 7.5 pEC50 34
pEC50 7.5 [34]
(R,S)-4-PPG Hs Full agonist 6.7 pEC50 11-12,34
pEC50 6.7 [11-12,34]
L-AP4 Rn Full agonist 6.2 pEC50 28
pEC50 6.2 [28]
L-CCG-I Rn Full agonist 6.2 pEC50 28
pEC50 6.2 [28]
D-AP4 Hs Full agonist 5.5 pEC50 38
pEC50 5.5 [38]
eglumegad Hs Full agonist 5.1 pEC50 21
pEC50 5.1 [21]
ACPT-I Rn Partial agonist 5.1 pEC50 5
pEC50 5.1 [5]
(1S,3R)-ACPD Hs Full agonist 4.4 pEC50 38
pEC50 4.4 [38]
(1S,3R)-ACPD Rn Full agonist 4.3 pEC50 28
pEC50 4.3 [28]
L-AP4 Hs Full agonist 7.0 – 7.2 pIC50 21
pIC50 7.0 – 7.2 [21]
L-SOP Hs Full agonist 6.2 – 7.2 pIC50 21,38
pIC50 6.2 – 7.2 [21,38]
L-CCG-I Hs Full agonist 6.1 – 6.3 pIC50 21
pIC50 6.1 – 6.3 [21]
L-glutamic acid Hs Full agonist 5.0 – 5.7 pIC50 21,38
pIC50 5.0 – 5.7 [21,38]
View species-specific agonist tables
Agonist Comments
(S)-3,4-DCPG is the only selective agonist for mGlu8. Affinity is 100 fold higher than on mGlu4 and mGlu6. L-AP4, L-SOP, (RS)-4-PPG are selective for group III mGlu receptors.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CPPG Rn Antagonist 6.3 pKi 25
pKi 6.3 [25]
LY341495 Hs Antagonist 6.8 pIC50 15
pIC50 6.8 [15]
MAP4 Rn Antagonist 5.1 – 7.6 pIC50 25,28
pIC50 5.1 – 7.6 [25,28]
DCG-IV Hs Antagonist 5.5 pIC50 21
pIC50 5.5 [21]
MSOP Rn Antagonist 5.3 pIC50 26
pIC50 5.3 [26]
MPPG Hs Antagonist 4.33 pIC50 38
pIC50 4.33 (IC50 4.65x10-5 M) [38]
View species-specific antagonist tables
Antagonist Comments
There is no specific mGlu8 antagonist.
CPPG, α-MSOP, MAP4 are group III selective antagonists.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
AZ12216052 Hs Positive 6.0 pEC50 6
pEC50 6.0 (EC50 1x10-6 M) [6]
Allosteric Modulator Comments
Reference [7] uses AZ12216052 and states that the compound may not mediate all effects via mGlu8 and not all behavioural effects are lost in mGlu8 KO mice; off target activity may be an issue.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  In RGT and CHO cells stably transfected with recombinant rat or human mGlu8 receptors.
References:  9,28,38
Tissue Distribution
Olfactory bulb, piriform cortex, pontine nuclei > neocortex, reticular thalamic nucleus, basolateral amygdaloid nuclear group.
Species:  Human
Technique:  in situ hybridisation.
References:  4
Olfactory bulb (granule cells, mitral cells), olfactory tubercule, mammillary body, retina.
Species:  Mouse
Technique:  in situ hybridisation.
References:  9
Superficial layer of the olfactory tubercle, piriform cortex, periamygdaloid cortical region.
Species:  Rat
Technique:  Immunohistochemistry.
References:  37
Retina.
Species:  Rat
Technique:  immunocytochemistry.
References:  17
Pancreatic islets (alpha cells).
Species:  Rat
Technique:  RT-PCR.
References:  36
Enteric nervous system.
Species:  Rat
Technique:  RT-PCR, Western blotting and immunocytochemistry.
References:  35
Basal ganglia: reticular thalamic nucleus > premotor cortex > nucleus accumbens > anteroventral thalamus, parafasicular nucleus, substantia nigra pars compacta, striatum, subthalamic nucelus > entopeduncular nucleus, globus pallidus, substantia nigra pars reticular, ventrolateral thalamus, ventromedial thalamus.
Species:  Rat
Technique:  in situ hybridisation.
References:  22
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR and Western blotting.
References:  1
Olfactory bulb (granule cells, mitral cells), piriform cortex (pyramidal cells), pontine gray, lateral reticular nucleus of the thalamus and other nuclei of basal ganglia > cerebral cortex, hippocampus, cerebellum, mammillary body.
Species:  Rat
Technique:  in situ hybridisation.
References:  28
Presynaptic active zone of both excitatory and GABAergic axon terminals.
Species:  Rat
Technique:  Western blotting.
References:  10
Presynaptic active zone of GABAergic axon terminals.
Species:  Rat
Technique:  immunocytochemistry.
References:  16
Nodose ganglia and nucleus solitary tract.
Species:  Rat
Technique:  RT-PCR
References:  14
Hippocampus: presynaptic terminals of the lateral perforant path in the dendate gyrus and CA3 regions.
Species:  Rat
Technique:  Immunohistochemistry.
References:  32
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Measurement of GIRK-mediated K+ currents in Xenopus oocytes transfected with the mGlu8 receptor.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of K+ currents.
References:  28
Measurement of cAMP levels in RGT cells transfected with the mGlu8 receptor.
Species:  Human
Tissue:  RGT cells.
Response measured:  Inhibition of cAMP accumulation.
References:  38
Measurement of IP levels in HEK 293 cells transfected with the mGlu8 receptor and Gqi9.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IP formation.
References:  5
Measurement of N-type Ca2+ currents in superior cervical neurons transfected with the mGlu8 receptor.
Species:  Rat
Tissue:  Superior cervical neurons.
Response measured:  Inhibition of N-type Ca2+ currents.
References:  13
Physiological Functions
Inhibition of synaptic transmission at lateral perforant path input to dendate gyrus.
Species:  Mouse
Tissue:  Brain
References:  3,39
Modulation of the fast component of the dorsal root-evoked ventral root potential.
Species:  Rat
Tissue:  Spinal Cord
References:  34
Inhibition of sound-induced seizures in DBA/2 mice
Species:  Mouse
Tissue:  Brain
References:  23
Modulation of synaptic transmission in the retino-collicular pathway.
Species:  Rat
Tissue:  Brain
References:  27
mGlu8 stimulation induces c-Fos in stress-related brain regions.
Species:  Mouse
Tissue:  Brain
References:  19
Regulation of transmitter release in the supraoptic nucleus of the rat hypothalamus.
Species:  Rat
Tissue:  Brain
References:  24
Attenuation of alcohol self-administration.
Species:  Rat
Tissue:  In vivo.
References:  2
Acquisition and expression of conditioned fear are inhibited by mGlu8 stimulation in the amygdala.
Species:  Rat
Tissue:  In vivo.
References:  30
Physiological Consequences of Altering Gene Expression
Increased anxiety-related behavior in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  8,20
Absence of inhibition of synaptic transmission at the perforant path by L-AP4 in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3,39
Absence of inhibition of synaptic transmission at the perforant path by DCPG in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  39
mGlu8 knockout mice exhibit an increased c-Fos expression in the thalamus following the elevated plus maze test.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  18
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0001417 decreased exploration in new environment PMID: 16045496 
Grm8tm1En Grm8tm1En/Grm8tm1En
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1351345  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 12213276 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0001522 impaired swimming PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0001363 increased anxiety-related response PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0001260 increased body weight PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0005458 increased percent body fat PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8
MGI:1351345  MP:0005331 insulin resistance PMID: 16045496 
Biologically Significant Variants
Type:  Splice variants.
Species:  Rat
Description:  Alternative splicing results in a different C-terminus.
References:  4
Type:  Splice variants.
Species:  Human
Description:  Alternative splicing results in a different C-terminus.
References:  21
Type:  Splice variants.
Species:  Human
Description:  A second splice variant introduces a stop codon before the 7 transmembrane domain resulting in a potentially secreted isoform of the receptor.
References:  21
Type: 
Species:  Rat
Description:  mGlu8 can be sumoylated.
References:  33
General Comments
Schoepp et al., (1999) [31] and Pin & Acher (2002) [26] review and compare the pharmacology of mGlu receptors.

REFERENCES

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13. Guo J, Ikeda SR. (2005) Coupling of metabotropic glutamate receptor 8 to N-type Ca2+ channels in rat sympathetic neurons. Mol Pharmacol67: 1840-1851. [PMID:15755905]

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15. Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD. (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology.37: 1-12. [PMID:9680254]

16. Kogo N, Dalezios Y, Capogna M, Ferraguti F, Shigemoto R, Somogyi P. (2004) Depression of GABAergic input to identified hippocampal neurons by group III metabotropic glutamate receptors in the rat. Eur J Neurosci19: 2727-2740. [PMID:15147307]

17. Koulen P, Kuhn R, Wassle H, Brandstatter JH. (1999) Modulation of the intracellular calcium concentration in photoreceptor terminals by a presynaptic metabotropic glutamate receptor. Proc Natl Acad Sci U S A.96: 9909-9914. [PMID:10449793]

18. Linden AM, Baez M, Bergeron M, Schoepp DD. (2003) Increased c-Fos expression in the centromedial nucleus of the thalamus in metabotropic glutamate 8 receptor knockout mice following the elevated plus maze test. Neuroscience.121: 167-178. [PMID:12946709]

19. Linden AM, Bergeron M, Baez M, Schoepp DD. (2003) Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice. Neuropharmacology.45: 473-483. [PMID:12907308]

20. Linden AM, Johnson BG, Peters SC, Shannon HE, Tian M, Wang Y, Yu JL, Koster A, Baez M, Schoepp DD. (2002) Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology.43: 251-259. [PMID:12213279]

21. Malherbe P, Kratzeisen C, Lundstrom K, Richards JG, Faull RLM, Mutel V. (1999) Cloning and functional expression of alternative spliced variants of the human metabotropic glutamate receptor 8. Brain Res. Mol. Brain Res.67: 201-210. [PMID:10216218]

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To cite this database page, please use the following:

Francine Acher, P. Jeffrey Conn, Robert Duvoisin, Francesco Ferraguti, Peter J. Flor, David Hampson, Michael P. Johnson, James Monn, Shigetada Nakanishi, Ferdinando Nicoletti, Jean-Philippe Pin, Darryle D. Schoepp, Ryuichi Shigemoto.
Metabotropic glutamate receptors: mGlu8 receptor. Last modified on 27/09/2013. Accessed on 16/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=296.

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